Cytochrome P450 (CYP) constitutes a multigene family of hemoproteins responsible for the metabolism of numerous xenobiotics including therapeutic drugs, environmental chemicals, and dietary constitutes, as well as endogenous substrates such as steroids and bile acids. Among the human CYP proteins, CYP3A is the most abundant cytochrome P450 isozyme and plays an important role in the oxidative metabolism of a number of widely used and clinically important drugs. It is estimated that approximately 50% of all currently used drugs are substrates for CYP3A, including steroids, HIV protease inhibitors, benzodiazepines, calcium channel blockers, cholesterol-lowering drugs, immunosuppressants, cancer chemotherapeutics, macrolide antibiotics, etc.
A marked interindividual variability of the catalytic function to metabolize CYP3A substrates has been demonstrated, exceeding 20-fold in some populations. The variability of CYP3A activity is assumed to reflect the combined effects of genetic and environmental factors. CYP3A activity can be readily modulated by inducers (e.g., rifampicin and anticonvulsant agents), and many potent inhibitors (e.g., azole antifungal agents and macrolide antibiotics). Metabolism involving CYP3A is also affected by liver disease, aging, gender, race, etc. Variation in CYP3A activity is particularly important for substrates with narrow therapeutic indices, such as cancer chemotherapeutics and immunosuppressants. The term “CYP3A-phenotyping” may be defined as an assessment of the CYP3A in vivo activity to metabolize a specific CYP3A substrate (whether it is endogenous or exogenous) in a subject in a certain state, condition, time, etc. CYP3A-Phenotyping in a human subject provides valuable information about actual and real-time enzyme activity in vivo to metabolize the substrate, which can allow prediction or assessment of his or her ability for metabolizing other CYP3A substrates as well. Hence, it can allow individualization of dosing of a certain CYP3A substrate drugs. Also, inadequate dosing can be avoided thereby. The phenotyping is also becoming an important aspect of drug development for predicting the potential inhibition or induction of CYP3A enzyme caused by new drugs (drug-drug interactions). Knowledge of the role of CYP3A in the metabolism of a putative drug candidate are desirable at an early stage in the drug development process, for assisting in the choice of the best drug candidate for further development.